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. 2016 Sep 6;11(9):e0162352.
doi: 10.1371/journal.pone.0162352. eCollection 2016.

Steroidogenic Factor 1 in the Ventromedial Nucleus of the Hypothalamus Regulates Age-Dependent Obesity

Ann W Kinyua  1 , Dong Joo Yang  1 , Inik Chang  2 , Ki Woo Kim  1   3
Affiliations

Steroidogenic Factor 1 in the Ventromedial Nucleus of the Hypothalamus Regulates Age-Dependent Obesity

Ann W Kinyua et al. PLoS One. .

Abstract

The ventromedial nucleus of the hypothalamus (VMH) is important for the regulation of whole body energy homeostasis and lesions in the VMH are reported to result in massive weight gain. The nuclear receptor steroidogenic factor 1 (SF-1) is a known VMH marker as it is exclusively expressed in the VMH region of the brain. SF-1 plays a critical role not only in the development of VMH but also in its physiological functions. In this study, we generated prenatal VMH-specific SF-1 KO mice and investigated age-dependent energy homeostasis regulation by SF-1. Deletion of SF-1 in the VMH resulted in dysregulated insulin and leptin homeostasis and late onset obesity due to increased food intake under normal chow and high fat diet conditions. In addition, SF-1 ablation was accompanied by a marked reduction in energy expenditure and physical activity and this effect was significantly pronounced in the aged mice. Taken together, our data indicates that SF-1 is a key component in the VMH-mediated regulation of energy homeostasis and implies that SF-1 plays a protective role against metabolic stressors including aging and high fat diet.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Metabolic phenotypes of young and old VMH-specific SF-1 KO mice.
(A and E) percentage body weight, (B and F) daily food intake, (C and G) blood insulin levels, (D and H) blood leptin levels. (A-D) 20–30 weeks old male mice. (E-H) 45–55 weeks old male mice. The number of animals examined is expressed in the parenthesis. The data are represented as mean ± SEM (*P < 0.05, Student’s t-test).
Fig 2
Fig 2. Regulation of energy expenditure by SF-1 in metabolic stress condition.
(A) O2 consumption, (B) heat generation, (C) ambulatory movement, (D) rearing movement, (E) body weight, (F) blood insulin levels, (G) blood leptin levels, (H) glucose levels. (A-D) 45–55 weeks old male mice. (E-H) 20–30 weeks old male mice challenged with high fat diet for three weeks. Figures in parenthesis indicate number of animals studied. The data are represented as mean ± SEM (*P < 0.05, Student’s t-test for bar graphs and two-way ANOVA for comparison of multiple time points). BB, beam break.
Fig 3
Fig 3. Impaired energy expenditure in SF-1 KO mice under high fat diet.
(A and B) O2 consumption, (C and D) CO2 production, (E and F) heat generation. (A-F) 20–30 weeks old male mice. Figures in parenthesis indicate number of animals studied. The data are represented as mean ± SEM (*P < 0.05, Student’s t-test). HFD, high fat diet.
Fig 4
Fig 4. Effect of SF-1 deletion on glucose homeostasis.
(A and D) fed and fasted glucose levels, (B and E) glucose tolerance test (GTT), (C and F) insulin tolerance test (ITT). (A-C) 20–30 weeks old female mice. (D-F) 45–55 weeks old female mice. The number of animals examined is expressed in the parenthesis. The data are represented as mean ± SEM (*P < 0.05, Student’s t-test).
Fig 5
Fig 5. SF-1 deletion leads to impaired gene expression in BAT and blunted Vglut2 expression in the VMH.
(A) UCP1, (B) β3AR, and (C) PPARγ expression in brown adipose tissue (BAT) in young male mice (12 weeks). (D) In situ hybridization analyses of Vglut2 expression in the VMH. The number of animals examined is expressed in the parenthesis. Scale bar = 200μm, The data are represented as mean ± SEM (*P < 0.05, Student’s t-test).
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Grants and funding

This work was supported by Small and Medium Business Administration (Technological Innovation R&D Program S2178403), National Research Foundation (2016R1C1B3012748 and 2014K1A3A1A19066980 for K.W.K. and 2016R1A5A2008630 for I. C.), and Global PhD Fellowship (NRF-2015H1A2A1032009 for D. J. Y.).